TETRAHEDRON LETTERS Tetrahedron Letters 44 (2003) 9299–9302 Pergamon Ring opening reactions of quinoline substituted epoxides Andrew N. Boa,* Stephen Clark, Paul R. Hirst and Robert Westwood † Department of Chemistry, University of Hull, Cottingham Road, Hull HU67RX, UK Received 4 September 2003; revised 3 October 2003; accepted 10 October 2003 Abstract—6-Oxiranyl- and 3-oxiranyl-2-phenylquinoline-4-carboxylic acid diisopropylamides react with secondary amines and lithium amides to give (aminohydroxyethyl)quinolines but with opposite regioselectivities. Upon epoxidation of 3-formylquinoline 2 a 5:1 mixture of atropisomers is formed. This ratio is maintained upon epoxide ring-opening with amines in ethanol at reflux, but with lithium amides at room temperature a 1.3:1 ratio of isomers is obtained. © 2003 Elsevier Ltd. All rights reserved. Brequinar sodium is a quinoline-4-carboxylate deriva- tive originally described 1 by researchers at DuPont (Fig. 1). This molecule has been shown to be an inhibitor of human dihydroorotate dehydrogenase (DHOdehase), the fourth enzyme involved in the biosynthetic pathway to pyrimidine nucleotides in prokaryotic and eukaryotic organisms. 2 As such, selec- tive inhibitors of this enzyme have a wide range of potential therapeutic applications 3 although develop- ment of brequinar as an anticancer agent was halted due lack of efficacy at doses where toxic effects began to appear. We have however been preparing and screening brequinar-related compounds to probe the active site of DHOdehase from a variety of organisms. 4 During the early part of this work we prepared the aldehydes 1 and 2 via free radical bromination followed by oxidation 5 of the corresponding methyl substituted 2-phenylquinoline-4-carboxamide. These aldehydes were chosen to serve as one of several versatile precur- sors to a wide range of 3- and 6-substituted quinolines. Conversion of the aldehydes 1 and 2 to their corre- sponding epoxides 3 and 4 proceeded cleanly using dimethylsulphonium methylide in tert -butanol at 30°C (Scheme 1). 1 H NMR showed epoxide 3 to be a 1:1 mixture of diastereoisomeric conformers, distinguish- able on the NMR timescale due to the restricted rota- tion about the C Ar CO bond. The 1 H NMR of epoxide 4 however showed a mixture of isomers rang- ing from about 5 to 6:1. In 2-substituted 1-naphthoic acid diisopropylamides the rotation about the C Ar CO bond is heavily restricted, 6 so the related diisopropyl- amide 4 can be considered to be a mixture of atropisomers 7 (diastereoisomeric conformers with a half-life of 1000 s or more). Clayden 6 has invoked a non-chelation controlled path- way to explain the reactivity of 2-formylnaphthalene-1- Figure 1. Brequinar sodium. Scheme 1. Keywords : regioselective; epoxide; amino alcohol; atropisomers. * Corresponding author. Tel.: +44-1482 465022; fax: +44-1482- 466410; e-mail: a.n.boa@hull.ac.uk † Current address: Cyclacel Limited, James Lindsay Place, Dundee Technopole, Dundee DD1 5JJ, UK; bwestwood@cyclacel.com 0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2003.10.062